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Nuclear Factor Kappa-B: Bridging Inflammation and Cancer
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Mohammad Aslam Khan, Girijesh Kumar Patel, Haseeb Zubair, Nikhil Tyagi, Shafquat Azim, Seema Singh, Aamir Ahmad, Ajay Pratap Singh
Inhibition of NF-κB activation could be achieved by inhibiting kinase activity of IKK with the specific inhibitors of IKKα and/or IKKβ. Irreversible inhibitors, BAY 11-7082 and BAY 11-7085, block phosphorylation of IκBα, suppress proteasomal degradation of IκBα and inhibit NF-κB translocation to the nucleus. In vitro study suggested that BAY 11-7082 treatment blocks NF-κB activation and induces mitochondrial mediated apoptosis. Treatment with BAY 11-7082 downregulated the expression of cyclin A and CDK-2 and induced cell cycle arrest [155]. Another study suggested that BAY 11-7082 induces robust cell death in primary adult leukemic T cells, as compared to normal peripheral blood mononuclear cells (PBMCs), by inhibiting the activation of NF-κB [156]. BAY 11-7085 treatment potentiates the efficacy of cisplatin in ovarian cancer by downregulating the expression of X-linked inhibitor of apoptosis protein (XIAP) and suppressing tumor cell invasiveness [157]. Pham and colleagues suggested that BAY 11-7082 treatment blocked constitutive activation of NF-κB, and induced apoptosis in non-Hodgkin mantle cell lymphoma by downregulating expression of Bcl-XL and Bfl/A1 [158]. In pre-clinical study, it has been shown that colon cancer cells-bearing mice treated with BAY 11-7085 fail to develop tumor, as compared to vehicle treated mice [159]. Co-administration of BAY11-7085 with histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), reduces NF-κB in non-small cell lung cancer cells and induces enhanced apoptosis, as compared to single treatment [160].
Responses to Muscular Exercise, Heat Shock Proteins as Regulators of Inflammation, and Mitochondrial Quality Control
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Alex T. Von Schulze, Paige C. Geiger
Like HSP70, HSP25 is known to inhibit the activation of the pro-inflammatory transcriptional complex, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). HSP25-induced NF-κB inhibition is thought to occur by preventing the degradation NF-κB's upstream inhibitory regulator, the IκB kinase (IKK) complex (25, 45). It is believed that HSP25 blocks the phosphorylation of IKKβ, whose phosphorylation is critical for the degradation of the IKK complex (68). This inhibition of the IκB kinase complex formation (IKKα and IKKβ) causes a decrease in the phosphorylation of NF-κB inhibitor, IκB, which ultimately suppresses the activation of the NF-κB signalling pathway (45). As with HSP70, HSP25 can shift the cell away from inflammatory signalling. However, shifts in signalling are not the only ways that HSPs can prevent cell death and restore homeostasis.
Tyrosine Phosphatases as New Treatment Targets in Acute Myeloid Leukemia
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
I. Hubeek, K. Hoorweg, J. Cloos, Gertjan J. L. Kaspers
The novel compound carboxylic acid ertiprotafib was synthesized at Wyeth research and appeared to be a good PTP1B inhibitor in vivo (108). This compound even progressed to Phase II clinical trials for treatment of diabetes mellitus but was terminated in 2002 due to unsatisfactory efficacy and dose-limiting side effects. Further research elucidated that ertiprofatib improved glycemic control via several mechanisms (109). Recently, ertiprotafib was also shown to be a potent inhibitor of IkappaB kinase beta (IKKβ) (110).
Adipose Tissue Macrophage-Mediated Inflammation in Obesity: A Link to Posttranslational Modification
Published in Immunological Investigations, 2023
Dongqin Wei, Xin Tian, Xiangyun Zhai, Chao Sun
NF-κB is a multisubunit protein composed of RelA/p65, RelB, NFκB1/p105, NFκB1/p50, c-rel, NFκB2/p100 and NFκB2/p52. These proteins are the main targets for PTM (Figure 3) (Ghosh and Dass 2016). NF-kB is one of the important activating branches of many inflammatory cytokines, including lipopolysaccharide (LPS), IL-1, TNFα and IL-6. When the receptors TLR/IL1R are bound by the ligands LPS and IL-1, the adaptor molecule (MyD88) and IL-1 receptor-associated kinase 4 (IRAK4) will be recruited to the receptors. Activated IRAK4 can interact with TRAF6 through the TRAF domain to mediate the recruitment and activation of TRAF6 (Cohen and Strickson 2017). Activated TRAF6 and ubiquitin-conjugating enzyme 13 (Ubc13) together catalyze K63-linked polyubiquitination to mediate the activation of the MAPK kinase kinase (MAP3K) complex and Ikappa B kinase (IKK) (Deng et al. 2000; Wang et al. 2001). In addition, modification of receptor-interacting protein kinase 1 with K63 and linear ubiquitin chains can facilitate TNFα signaling to NF-κB activation through induced proximity of both transforming growth factor kinase 1 and IKK (Ea et al. 2006; Haas et al. 2009). IKK, responsible for inducing the phosphorylation of IκB, contains two catalytic subunits, IKKα and IKKβ, which can phosphorylate IκB correctly. This phosphorylation usually isolates NF-κB and prevents it from entering the nucleus (Karin and Ben-Neriah 2000; Viatour et al. 2005). At this time, the phosphorylated IκBs are degraded by modifying the K48-linked ubiquitin chain, thereby releasing RelA/p65 and inducing IL-6 mRNA expression (Iwasaki et al. 2011).
Emerging drug targets for colon cancer: A preclinical assessment
Published in Expert Opinion on Therapeutic Targets, 2022
Madison M. Crutcher, Trevor R. Baybutt, Jessica S. Kopenhaver, Adam E. Snook, Scott A. Waldman
IKK is an additional target in the NF-κB pathway. Activation of the canonical NF-κB pathways converge on activation of IKK formed by the kinase subunits IKKα, IKKβ, and a regulatory subunit, NEMO/IKKγ [33]. Drug-discovery efforts have focused on IKKβ as foundational mouse studies have suggested IKKβ and NEMO are essential, while IKKα is nonessential, for activation of the pathway. High-throughput screening has identified many natural compounds that directly inhibit the kinase activity of IKKβ. However, many of these compounds have off-target effects [34]. In one study, screening of a library of FDA-approved agents identified an anti-malarial drug with anti-NF-κB action. This drug suppressed NF-κB through IKK inhibition leading to apoptosis in CRC cells in vitro and in vivo [35].
Endostatin in fibrosis and as a potential candidate of anti-fibrotic therapy
Published in Drug Delivery, 2021
Zequn Zhang, Xi Liu, Zhaolong Shen, Jun Quan, Changwei Lin, Xiaorong Li, Gui Hu
Nuclear factor-κB (NF-κB), a transcription factor present in the cytoplasm in inactive heterodimeric or homodimeric form, regulates multiple cellular processes. Particularly, NF-κB has crucial roles in immune cell activation, inflammation, stress response, and apoptosis. Many stimuli can activate NF-κB, which translocates from the cytoplasm to the nucleus, driving the expression of genes that contain κB binding sites (Oeckinghaus & Ghosh 2009; Hoesel & Schmid 2013). The human NF-κB family is comprised of five cellular DNA-binding subunits: p50, p52, crel, relA, and relB. In general, NF-κB binds to its inhibitory IκB partner (IκBα, IκBβ, and IκBε) and does not show transcriptional activity. The IKK protein kinase complex (IKKα, IKKβ, and IKKγ) is the core link that regulates NF-κB signaling. NF-κB must be released from IκB for activation. The activation of NF-κB mainly comprises two pathways: the canonical pathway, which is initiated due to cytokines like IL-1(interleukin-1) and TNF-α; and the alternative pathway, which plays a crucial role in B lymphocytes (Hoesel & Schmid 2013).